Keywords

1.1 Introduction

Salivary gland neoplasms are the most morphologically and clinically diverse solid epithelial tumors. There are 25 distinct salivary gland tumor types in the current WHO classification [1]. Given the clinical and management focus of this text, descriptions of pathologic features will be limited to gross and histopathologic manifestations relevant to surgical and oncologic management. Similarly, brief lineage-related biomarkers and genetic findings are present. Although the main focus is on malignant entities, benign tumors with differential diagnostic importance and those with potential progression to malignancy are discussed.

1.2 Salivary Gland Development and Tumorigenesis

Salivary glands evolve from the stomatodial surface of embryo at 6–8 weeks through branching morphogenesis where progressive indentation and elongation of an epithelial cord through the underlying ectomesenchyme leads to the formation of the ductal acinar unit [2,3,4]. The inner cellular lining of the ductal segments is epithelial in lineage except for the terminal duct component in which both epithelial and basal/myoepithelial cells are present. This fundamental formation in large part linked to the putative segmental ductal derivation and diversity of salivary gland neoplasms [5]. In that context, the presence of myoepithelial cells plays a critical role in the structural polarity and stromal organization in tumors composed of both cell types. The mechanism for the dual epithelial-myoepithelial neoplastic participation in some tumors is uncertain. It is, however, possible that an event in uncommitted progenitor early in tumorigenesis gives rise to both epithelial and basal/myoepithelial cells (Fig. 1.1). In general, purely epithelial and majority of high-grade carcinoma arise from the main (nonterminal) ductal segments and those of low grade from the terminal duct-acinar unit.

Fig. 1.1
figure 1

Empirical diagram of the developmental pathway of the morphologic and cellular origins of salivary tumors

Full size image

1.3 Classification

Salivary gland tumors are broadly categorized into benign and malignant subtypes based on their histopathologic characteristics and the invasive nature of tumor at presentation. Grossly, benign tumors are well-circumscribed, thinly encapsulated, and soft to slightly firm in consistency. Histologically, generally these neoplasms display uniform epithelial and/or myoepithelial cell composition in variable manifestations. Malignant tumors, in contrast, present as firm, less mobile, ill-defined, and invariably infiltrative in nature. Histologically, tumors display heterogeneous neoplastic cellular and structural features (Table 1.1).

Table 1.1 Broad clinicopathologic categories of salivary gland carcinomas
Full size table

1.4 Pre-surgical Diagnosis of Salivary Gland Tumors

1.4.1 Fine Needle Aspirations (Table 1.2)

Initial assessment of salivary tumors commonly entails a fine needle aspiration cytology evaluation. The primary purpose of this procedure is to exclude metastasis, lymphoreticular disorders, infectious processes, and reactive lesions and to ascertain the primary salivary nature of mass. In general, the majority of primary and malignant tumors can be determined through this procedure. FNA, however, is limited in delineating benign and malignant nature of basaloid and oncocytic and myoepithelial and of carcinoma ex-PA. The procedure is also valuable as a follow-up tool for harvesting cells for ancillary testing [6,7,8,9,10,11].

Table 1.2 Cytology in salivary gland mass evaluation
Full size table

1.4.2 Core Biopsy

Occasionally, core biopsy is performed for salivary tumor diagnosis; however, this procedure should be limited to non-resectable, recurrent, and metastatic tumors.

1.4.3 Intraoperative Consultations

Although it is unnecessary, intraoperative frozen section can be requested where the nature of malignancy may alter the surgical plan and if surgical margins are of concern. In these instances, the surgeon and pathologist should be closely interacting during this process especially for minor salivary tumor resections. In these cases it is advisable that surgeons submit separate cavity-based margins.

1.5 Post Surgical Gross Assessment

Salivary tumor resections of major and minor glands should be inspected for gross infiltration of surrounding host tissue and processed to include tumor/host tissue interface and different regions of the tumor mass to assess invasion into peri-glandular soft tissue. Gross description of salivary resection should include size, appearance, and consistency, and the relation to surrounding host tissue is required.

1.5.1 Histopathologic Evaluation

Diagnosis for salivary gland tumors is based on the light-optic evaluation of well-prepared hematoxylin- and eosin-stained sections representing lesion and its boundaries. Certain immunomarkers may be used in certain instances for differential diagnosis and assessment of progression.

1.5.2 Pathologic Report

Pathology reports of salivary tumors must primarily include the following information: type of surgery, site, size, histologic diagnosis, presence or absence of perineural spaces, and margin status. Additional relevant findings may include grade if appropriate, and tumor diathesis, extraglandular extension margin status.

1.6 Common Benign Salivary Gland Tumors of Differential Diagnostic Significance

Benign salivary gland tumors are the most common in the parotid gland, and the vast majority pose no diagnostic difficulties. Certain subtypes may pose diagnostic challenges especially on the initial FNA evaluation. Generally, adenomas present as well-defined and encapsulated mass.

1.6.1 Pleomorphic Adenoma (PA)

PA is the most common benign salivary neoplasm and manifests a wide range of cellular and stromal component manifestations within and between tumors. Not uncommonly rare features such as squamous, sebaceous, and adipose tissue metaplasias are present, and this may lead to differential diagnostic challenges. PA generally presents as an ill-defined presentation and may manifest microscopic satellite formations that evade detection at the time of surgery leading to frequent recurrences. Histologically, tumors can be predominantly myoepithelial, epithelial, or paucicellular and can mostly be composed of chondroid, fibrotic, or myxoid elements. Occasionally, the delineation between myoepithelial dominant PA and myoepithelioma is difficult, but such distinction is of minimal clinical impact. Pleomorphic adenomas are also prone to recurrence and rarely distant dissemination. Metastasizing PA, in general, is histologically benign and typically presents in patients with multiple recurrence as a result of dislodgment of tumor in vascular spaces. These cases should be managed based on their presentation. Because of the not uncommon occurrence of carcinoma in long-standing PA, extensive sampling and careful examination of these tissues are critical especially in elderly patients with long-standing history of salivary swelling [12,13,14,15].

1.6.2 Myoepithelioma

Myoepithelial tumors are either entirely or largely composed of myoepithelial cells in spindle, plasmacytoid, and epithelioid features. The benign and malignant forms cannot be distinguished by FNA due to similar histologic features. Only on complete surgical excision the distinction of benign and malignant forms can be made. Immunohistochemistry may aid in confirming the diagnosis using SMA, p63, and calponin [16,17,18]. Their management is similar to pleomorphic adenoma.

1.6.3 Basal Cell Salivary Adenoma

Basal cell salivary tumors are composed of monotonous basal-like cells and classified into adenoma and adenocarcinoma based on the state of tumor invasion. Therefore, the initial assessment of these tumors by FNA is difficult if not impossible. Although the majority is cured by surgery, some adenomas may recur locally. Metastatic dermal basal cell carcinoma may lead to differential diagnostic difficulty especially in patients with remote history of skin primary. In these instances, immunostaining for keratin, p63, and SMA may confirm the dual cell formation of salivary basal neoplasms. Rarely, recurrence may develop due to multifocality. Not uncommonly, basaloid adenocarcinoma may evolve from adenoma [19,20,21].

1.6.4 Oncocytic Salivary Lesion

Oncocytic lesion/tumors are unique entities composed of mitochondrial-rich cells and are classified into hyperplastic and neoplastic lesions. The hyperplastic form is typically diagnosed as nodular oncocytic hyperplasia and may present unilaterally or bilaterally. These lesions regardless of their histologic classification are composed of monotonous epithelial cells with abundant eosinophilic cytoplasm and central nuclei. Histologic examination reveals the multinodular formation in variable sizes. The neoplastic types are classified into adenoma and carcinoma based on the status of the invasiveness [22,23,24].

1.6.5 Warthin’s Tumor (WT)

Warthin’s tumor can be presented bilaterally as single mass and rarely multifocally within intraparotid lymph nodes. The differential diagnosis of Warthin’s tumors should be considered in oncocytic tumors and mucoepidermoid carcinoma, especially on FNA materials. Thorough examination of Warthin’s tumors must be performed to exclude the latter possibility. Grossly, Warthin’s tumor presents as a brown bulging and pliable soft mass. Histologically, lesions are formed of eosinophilic epithelial cell lining lymphoid nodules in distinct structural formation [25,26,27].

1.7 Malignant Salivary Tumors

1.7.1 Mucoepidermoid Carcinoma (MEC)

MEC is the most common salivary carcinoma of minor and major salivary glands in adults and children. MEC is also the only salivary cancer where histologic grading is associated with clinical behavior. Accurate diagnosis is difficult on FNA material and can be confused with cystic lesions and Warthin’s tumor. Grossly, MEC presents as ill-defined cystic, partially cystic, or solid light tan and mucinous. Histologically, tumors are composed of mucinous, epidermoid (epithelial squamous-like), and transitioned (intermediate) cells in variable structural forms. Tumors are graded into low grade (grade 1), intermediate (grade 2), or poorly differentiated (grade 3) based on the extent of cystic and cellular manifestations. MEC may display oncocytic, clear, and transitional cell features of invariable proportion and patterns and display sclerotic. Mucoepidermoid carcinoma can rarely be associated with protracted radioactive iodine treatment in patients with papillary thyroid carcinoma. Low-grade cystic MEC is cured by complete surgery in major salivary gland. The most common grade is grade 2 where subjectivity plays a major role. Regardless of the reported grading systems, broadly speaking low-grade MECs are mainly cystic with limited foci of cellular proliferation, while intermediate grade displays more cellular formations with less cystic structure and the high-grade manifests markedly cellular with no cystic formation and focal intracellular mucin production [28,29,30,31,32].

Minor salivary gland MECs may pose surgical challenges if incompletely excised. Ancillary staining is rarely used in the diagnosis. Occasionally mucicarmine stain can be helpful in the diagnosis of poorly differentiated tumors. MEC is characterized by reciprocal translocations of chromosome 11p and 19q that lead to the formations of the CTRC1-MAML-2 fusion transcript [33,34,35]. Currently, there is no diagnostic, prognostic, and/or therapeutic validated evidence for this event. Mucoepidermoid carcinoma rarely shows keratin formation. Carcinoma with distinct keratin component and mucinous differentiation should be categorized as adenosquamous carcinoma. If metastasis is excluded, definitive distinction between these tumors should not influence the surgical management.

Complete surgical excision with free margins is the primary treatment for all grades of MEC. Post-operative XRT may be considered in case with close surgical margins and /or perineural invasion [32].

1.7.2 Adenoid Cystic Carcinoma (ACC)

ACC is the second most common and relentless salivary carcinoma subtype. ACC is assumed to develop from the terminal segment of the ductal-acinar unit and is formed of dual cell composition of outer myoepithelial and inner ductal cells [36]. The initial FNA diagnosis may not reliably be achieved, and definitive diagnosis can only be made on either excision biopsy, especially of minor salivary glands, or post-excision [37]. ACC is not graded due to the invariable presence of at least two histologic forms in any given tumor [38]. The tubular and the cribriform are composed of dual epithelial and myoepithelial cell. These forms retain the structural polarity, and pursue slow and progressive clinical course. Loss of myoepithelial component leads to epithelial solid form [39].

Solid epithelial development is typically associated with loss of myoepithelial cells and clinical progression. Solid myoepithelial transformation is typically of low-grade nature. ACC is characterized by translation between chromosomes (6;q) and (8;q) resulting in fusion genes of MY13 and MYBL1 genes with the NFIB genes in more than 60% of tumors. No definitive association between fusion and outcome has been established [40,41,42,43,44,45]. ACC of minor salivary glands, particularly the sin0-nasal sites, is difficult to eradicate unless clear margins are achieved intraoperatively.

1.7.3 Salivary Duct Carcinoma (De Novo and Ex-pleomorphic Adenoma)

Salivary duct carcinoma is one of the most aggressive malignancies of salivary glands and presents as de novo primary or as a malignant transformation of pleomorphic adenoma [46,47,48,49]. It is important that the carcinoma subtype be clearly stipulated in the diagnosis of this entity ex-PA. Generally, tumors histopathologically resemble high-grade mammary adenocarcinoma and share overlapping molecular and biomarker characteristics, an issue of differential diagnostic relevance in female patient. Multiple cytomorphologic features have been described including oncocytic, apocrine, rhabdoid, and squamoid. These morphologic forms have no clinical significance. SDC typically presents at high stage and wide surgical excision with neck lymph node dissection with radiotherapy and/or chemotherapy is the primary management [50,51,52].

Certain biomarkers may aid non-surgical therapy of these tumors including EGFR, AR and PTEN, and HER-2 [53, 54]. High AR nuclear expression is found in approximately 70% of males and 50% of female tumors. Recently, presence of AR isoform A7 has also been reported in AR-positive tumors of male and females [55,56,57]. Androgen deprivation treatment has been empirically used with variable and inconsistent results. PTEN expression is frequently lost in SDC and directly or indirectly is associated to PI3K pathway activation [58, 59].

1.7.4 Polymorphous Adenocarcinoma (PAC)

In the current WHO classification of head and neck tumors, the “low-grade” designation has been omitted due to the aggressive behaviors of some of these tumors. As the descriptive term implies, the tumor manifests variable neoplastic manifestation including lobular, trabecular, papillary, microcystic, and/or solid features. PAC is the second most common malignancy in the oral cavity, palate, and base of the tongue [60,61,62,63]. PAC has also been reported to occur in major salivary glands, the lacrimal gland, minor glands of the nasopharynx, and the nasal cavity. Grossly tumor presents as unencapsulated, light tan and soft with variable appearance and occasional hemorrhagic regions. A salient morphologic feature is the presence of distinctive cellular structures (eddy-like formation) along with the tubular, trabecular, and/or lobular structure. A reported subset with dominant cribriform and microcytic patterns has been reported as a separate entity but currently represents a variant of PAC [64]. Although a majority of these tumors pursue a good behavior with complete excision, not uncommonly recurrent and metastatic disease is encountered especially those of minor glands and base of tongue locations. This entity can be misclassified as adenoid cystic and epimyoepithelial carcinomas due to occasional overlapping features and definitive distinction may not be possible on small materials. Definitive diagnosis may not be achieved on biopsy materials and should not affect the surgical management. Rarely PAC may undergo high-grade undifferentiated transformation, and these cases typically pursue a more aggressive behavior [39, 65].

1.7.5 Acinic Cell Carcinoma

Acinic cell carcinoma is a distinctive entity composed of neoplastic cells of acinar cell features and coarse granules and afflicts a wide age range with no significant sex predilection. Acinic cell carcinoma is the second most common cancer in children and occurs mainly in the parotid and occasionally in mixed serious and mucinous glands. The tumor may rarely be encountered in mixed major and minor salivary glands [66,67,68]. Acinic cell carcinoma, as in Warthin’s tumor and oncocytic and mucoepidermoid carcinoma, may develop in intraparotid lymph nodes and can be multifocal. Grossly acinic cell carcinoma is typically well-circumscribed with a brownish, mahogany color, soft, and can be cystic. Histopathologically, they are readily recognized by well-trained pathologists and may display variable phenotype patterns microcystic followed by macrocystic with papillary formation. In general, acinic cell carcinoma has a low to intermediate grade but occasionally displays solid transformation and poor differentiation. Patients with high grade transformation should be managed as other high salivary carcinomas [67, 69, 70].

1.7.6 Secretory Carcinoma

Secretory carcinoma is a newly recognized subtype with similar morphology to their mammary gland counterpart. This new entity has been extracted from acinic cell carcinoma following the recognition of a morphologically similar subset of secretory carcinoma in a review of acinic cell carcinomas of the mammary gland [71, 72]. As in mammary and acinic cell carcinomas, they are low to intermediate in grade and typically managed similarly to acinic cell carcinoma. A subset of this entity, as in mammary tumors, manifests (12, 15) resulting in gene fusion transcript of the ETV6 and the NTRK3 genes [73,74,75]. Although this fusion has not been reported in other salivary gland carcinomas, it has been detected in multiple tumor entities of diverse cell origins including carcinoma, lymphoma, thyroid, and rare lung tumors. The incorporation of this fusion in the diagnosis and differential diagnosis of primary and metastatic salivary tumors must supersede the morphologic diagnosis. The diagnostic and biological significance of this fusion is currently uncertain and must await large studies with long-term follow-up. The clinical course and management is similar to acinic cell carcinoma [76].

1.7.7 Adenocarcinoma: Not Otherwise Specified (NOS)

Adenocarcinoma, NOS, is defined as a salivary gland malignancy with ductal and glandular features that cannot be categorized as epithelial salivary carcinomas. This entity includes adenocarcinoma, NOS, cribriform adenocarcinoma, and mucinous, papillary, and intestinal carcinoma subtypes. The majority of tumors are of parotid origin, but minor and major salivary glands can be the source. In general, they can be considered intermediate in grade and behavior. Surgical excision remains to be the primary treatment [77,78,79,80].

1.7.8 Basal Cell Adenocarcinoma (BCAC)

BCAC, a distinctive low-grade malignancy of salivary glands, is characterized by uniform basaloid cell composition forming ductal, acinar, and tubular structures. Their pathologic classification into benign and malignant forms is based on the presence of lack of infiltrative extension into host tissue. BCAC may present as de novo or as carcinoma arising from basal cell salivary adenoma especially the membranous form [81,82,83]. Some of these tumors share striking resemblance to dermal adnexal tumors, and both types of tumors may occur in the same patient. Tumors should be differentiated from metastatic basal cell carcinoma of the skin, and sialoblastoma in infants. Complete excision with clear margins is generally curative. Recurrence may occur if close margins or satellite nodules are reported. Neck dissection is rarely recommended. Not uncommonly, carcinoma may arise from pre-existing adenoma and may manifest high-grade features. Patients with these tumors should be managed similar to a high-grade salivary malignancy.

1.7.9 Clear Cell Carcinoma (CCC)

CCC is a rare entity typically composed of clear epithelial cells with and without fibrosis. Among tumors that may exhibit significant clear cell features are mucoepidermoid, oncocytic, and myoepithelial carcinomas. Grossly, tumors are generally less well-circumscribed, soft, and tan with and without visible sclerosis. The most common site for these tumors is the oral cavity. Females are thought to be more affected than males, but the rarity of these tumors precludes confirmation. Complete excision of this low−/intermediate-grade tumor is curative. Rarely nodal metastasis and recurrence may occur [84,85,86,87].

1.7.10 Myoepithelial Carcinoma

Myoepithelial carcinoma, similar to myoepithelioma, is composed entirely of malignant myoepithelial cells of hybrid epithelial and smooth muscle characteristics. Pre-surgical classification into benign and myoepithelial-rich PA may not be possible by FNA screening. Grossly, tumors are generally ill-defined, gray to tan in color, and firm in consistency. Histopathologically, they may display spindle, epithelioid, plasmacytoid, and/or mixed cell composition with infiltrative and ill-defined boundaries. The differentiation from the benign tumor is largely based on the infiltrative nature and extension into surrounding soft tissue. Myoepithelial carcinoma presents either in a pure form or as the malignant component of long-standing pleomorphic adenomas. These tumors are generally low grade and managed by complete surgical excision. Infiltrative spindle cell forms can be prone to recurrence [88,89,90,91].

1.7.11 Epithelial-Myoepithelial Carcinoma (EMC)

EMC is a low-grade salivary malignancy composed of dual cell types; outer clear myoepithelial and inner epithelial cells in ductal and nesting formation. EMC is uncommon with an estimated incidence of 5% of salivary malignancies. The most common sites of these tumor types are the parotid and the submandibular glands. The majority is of low-intermediate grade and is generally cured by complete surgical excision. Because of their dual cell formation, they may cause differential diagnostic difficulties with adenoid cystic, myoepithelial, and clear cell carcinomas. High-grade transformation has been reported and should be managed as high-grade malignancy [92,93,94].

1.7.12 Carcinosarcoma

Carcinosarcoma is a rare salivary malignancy composed of two distinct high-grade epithelial carcinoma and heterologous mesenchymal derived components. The epithelial form in commonly high-grade adenocarcinoma and the mesenchyme form is osteo-chrondro rhabdo and/or angiosarcoma subtypes. Tumors are large and grossly variable with solid, hemorrhagic, and osteo-chondromatous features with extension into surrounding host tissue. Generally, they are de novo in presentation but may rarely originate from pleomorphic adenoma and both instances are managed in a multidisciplinary setting. These tumors should be considered high-grade malignancy and if not surgically eradicated can be managed by either sarcoma or carcinoma medical oncology [95,96,97,98].

1.7.13 Poorly Differentiated and Undifferentiated Carcinomas

Primary poorly differentiated carcinoma may exhibit either small (slightly larger than lymphocytes) or large cell formation typically in cohesive sheets and nests. These tumors may manifest neuroendocrine differentiation and can be diagnosed as poorly differentiated carcinoma with neuroendocrine features or small- and large-cell neuroendocrine carcinoma. The latter tumors, particularly, should be differentiated from metastatic or unknown primary Merkel cell carcinoma. Tumors typically run aggressive clinically and frequently show lymph node metastasis. Management remains to be initial surgery with postoperative XRT and/or chemotherapy [99,100,101].

1.7.14 Undifferentiated (Lymphoepithelial) Carcinoma

Morphologically these tumors mimic nasopharyngeal carcinoma and are rare in Caucasian populations. Tumor is characteristically composed of malignant epithelial cells forming synthetial nests with intra- and peritumoral lymphoid infiltrate of undifferentiated tumor cells. Primary intraparotid tumor may arise de novo or from lymphoepithelial lesions. Tumor may or may not be positive for EBV. The tumor may present with lymph node metastasis. Surgical treatment is the primary approach with postoperative radiation and/or chemotherapy [102,103,104,105].

1.7.15 Primary Squamous Carcinoma

Primary squamous carcinoma of the salivary gland is exceedingly rare, and the diagnosis mostly only is made after the exclusion of dermal squamous malignancy even if remote. Primary squamous carcinoma can rarely occur in patients with long-standing sialolithiasis and chronic inflammation and squamous metaplasia of the main duct that primary squamous diagnosis can develop. The differential diagnosis from tumors with squamous features includes MEC and salivary duct carcinomas. Proximity to the main duct with evidence of squamous metaplasia and/or dysplasia is necessary to confirm the primary origin. Typically they are well to moderately differentiated and their surgical excision is curative [106,107,108].

1.7.16 Sialoblastoma

This is a tumor of infancy and has, until recently, been considered of uncertain malignant potential. In the fourth WHO edition of H&N tumor classification, it was considered low-grade malignant neoplasm of infancy. Histologically, tumors manifest basal cell proliferation with remarkable resemblance to salivary gland anlage.

This entity shares common cellular features with basaloid salivary tumors and adenoid cystic carcinoma. Their presentation at birth or shortly afterward is critical to proper classification. Complete surgical excision is curative in most cases. Recurrence and nodal metastasis have been reported in approximately 25%. Rare instance of concurrent presentation with hepatoblastoma and congenital nevi has been reported [109,110,111,112].